EA039150B1 - New oral formulations of belinostat - Google Patents

Abstract

The invention relates to new formulations of belinostat suitable for oral administration, a process of preparation thereof, pharmaceutical compositions comprising said formulations and uses thereof.

Description

The invention relates to a new oral formulation based on belinostat.

Prerequisites for the creation of the invention

Belinostat is a histone deacetylase inhibitor (HDAC inhibitor) with a sulfonamide hydroxamide structure. The chemical name of belinostat is (2E)-N-hydroxy-3-[3-(phenylsulfamayl)phenyl]prop-2-enamide. Its structural formula is as follows:

Belinostat is marketed as Beleodac®, a sterile yellow powder for injection containing 500 mg of belinostat as the active ingredient. Each ampoule also contains 1,000 mg of L-Arginine, USP, as an inactive ingredient. It is intended for intravenous administration after reconstitution with water. The powder is mixed with 9 ml of sterile water for injection, and the reconstituted solution is further diluted with 250 ml of sterile 0.9% sodium chloride solution for injection before infusion. Beleodac® is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Its recommended dosage is 1000 mg/m ² administered over 30 minutes by intravenous infusion once a day on days 1-5 of a 21-day cycle. Cycles may be repeated every 21 days as long as the disease progresses or unacceptable toxicity occurs.

Administration by injection is burdensome for patients, and an oral form is generally desirable to facilitate patient compliance.

To allow for flexible dosing and combination regimens, an oral formulation of belinostat (a crystalline drug in capsules) has been developed and studied in clinical trials. Despite the discovery of clinical promise, the use of capsules with belinostat powder is limited due to the variability of the concentrations of the active substance achieved in the dose range from 250 to 2000 mg. In addition, high variability in oral belinostat clearance has been reported by Steele et al. (Cancer Chemother. Pharmacol., 2011, 67: 1273-1279) who investigated the pharmacokinetic and pharmacodynamic properties of oral belinostat administered as a crystalline powder in capsules with high doses of oral belinostat (up to 1000 mg/m ² for 5 consecutive days ).

This may be due to the poor physicochemical properties of belinostat, which has a low water solubility (0.14 mg/ml). In addition, belinostat is also extensively metabolized (especially by glucuronidation by UGT1A1 enzymes), which also leads to potentially significant variability (Wang et al., PLoS One. 2013;8(1):e54522).

In comparison, other clinically advanced hydroxamic acid-based HDAC inhibitors were originally developed as intravenous (IV) products, but have been further developed and marketed as oral solid dosage forms.

Worth noting is vorinostat

Vorinostat has poor water solubility (0.19 mg/mL), moderate permeability and has been reported to undergo extensive first pass metabolism in animal and human studies. The major pathways of vorinostat metabolism include glucuronidation and hydrolysis followed by β-oxidation. In the phase I trial, an absolute oral bioavailability of 43% was reported. Vorinostat (Zolinza®) is sold as a 100-mg capsule containing microcrystalline cellulose, croscarmellose sodium, and sodium stearate (vorinostat package insert).

Another hydroxam-based HDAC inhibitor is panobinostat lactate (Faridak®)

Anhydrous panobinostat lactate is slightly soluble in water. The solubility of panobinostat lactate in water is pH dependent with maximum solubility at pH 2 or 3 (~5 mg/mL), low solubility

- 1 039150 at neutral pH (0.3 mg/ml at pH 6.8) and very poor solubility at pH 7.6 (0.07 mg/ml). It penetrates well, but is extensively metabolized through the processes of reduction, hydrolysis, oxidation and glucuronidation. The absolute bioavailability of Faridak® is approximately 21%.

Panobinostat is sold as 10, 15 and 20 mg capsules containing magnesium stearate, mannitol, microcrystalline cellulose and pregelatinized starch (Panobinostat package insert).

Despite the fact that these molecules show physicochemical and pharmacokinetic properties similar to belinostat (poor solubility, high metabolism and poor to moderate oral bioavailability), they are successfully marketed for oral administration using conventional solid dosage forms such as as a simple mixture of powders in capsules.

Due to the specific variability in drug concentrations achieved and the limited bioavailability observed when using high doses of crystalline belinostat capsules, there is a need for a separate oral dosage form that provides increased bioavailability and, as a result, a potentially enhanced therapeutic effect.

In order to overcome the poor solubility of belinostat, which is a limiting factor for its absorption, various solubilization strategies have been tried. Among the methods of pH modification, the use of a co-solvent system, the formation of complexes with cyclodextrin, the formation of a salt with an acid or base in situ, and combinations thereof, the formation of a salt in situ has proved to be suitable for increasing the solubility of belinostat to a satisfactory level. However, the application of this approach is pharmaceutically unacceptable for the oral form due to the fact that the pH of the saturated solution was more than 9. In addition, Finn et al. (2016), The Discovery and Development of belinostat, in Successful Drug Discovery (eds. J. Fischer and W.E. Childers), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, chapter 3, reported poor chemical stability of belinostat in liquid solution at pH greater than 8.5. In the early preclinical stage, co-solvent preparations have been shown to achieve higher drug concentrations compared to the crystalline form, but they are also pharmaceutically unacceptable for these dosages due to the large amount of co-solvent.

As a consequence, it is very difficult to obtain a belinostat formulation that is physically and chemically stable and enhances the dissolution and oral bioavailability of belinostat. In addition, there is a need for an efficient and stable delivery system that can provide clinically acceptable oral administration of belinostat. Thus, it is an object of the invention to provide oral compositions comprising belinostat that have advantageous solubility, bioavailability and/or stability characteristics.

The essence of the invention

Surprisingly, it has been found that this goal can be achieved by a solid dispersion comprising belinostat in amorphous form and at least one non-ionizable (neutral) non-cellulosic polymer, such as a vinyl lactam polymer.

The challenge was to find a composition that would prevent recrystallization over time (good physical stability) and have good chemical stability, since molecules in the amorphous state can be prone to instability during storage due to their greater mobility in the amorphous state. . In addition to good solid state stability, the composition should also have an improved dissolution profile as a result of inhibition of crystallization from the supersaturated solution formed upon dissolution of the amorphous material.

As described below, it has been unexpectedly found that only a certain type of matrix compounds (polymers), namely non-ionizable (neutral) polymers, leads to increased solubility of belinostat in combination with satisfactory physical and chemical stability and increased bioavailability.

Detailed description

According to a first object, the invention relates to an amorphous solid dispersion (ASD) of belinostat comprising:

a) belinostat or a pharmaceutically acceptable salt, solvate or ester thereof;

b) at least one non-ionizable (neutral) non-cellulosic polymer; and

c) optionally at least one additive.

The term solid dispersion refers to a composition in the solid state, i. a state that is neither liquid nor gaseous, wherein the belinostat is dispersed in at least one pharmaceutically acceptable polymer contained in the solid dispersion. The term solid dispersion as used herein encompasses all known categories of solid dispersion types, ie. simple eutectic mixtures, solid solutions such as continuous solid solutions, discontinuous solid solutions, crystalline substitutions, interstitial crystalline and amorphous solid solutions, glassy solutions, and amorphous precipitates in crystalline supports. According to the invention, the solid dispersion is an amorphous solid dispersion (ASD).

As used herein, the term amorphous solid dispersion (ASD) refers to a dispersion of a drug substance in a solid polymer in an amorphous state. The term amorphous

- 2 039150 solid dispersion refers to solid dispersions, including belinostat, essentially in amorphous solid form. Preferably, the amorphous belinostat particles are dispersed in the polymer. The term substantially amorphous solid form is intended to mean that at least 80% by weight, typically at least 85% by weight, preferably at least 90% by weight, more preferably at least 95% by weight, even more preferably at least 96% by weight, more preferably at least 97% by weight, more preferably at least 98% by weight, more preferably at least 99% by weight, more preferably at least 99.9% by weight, more preferably all of the belinostat present in amorphous form. ASD consists of a mixture of a drug substance with a polymer to stabilize the amorphous drug substance.

Amorphous refers to the non-crystalline state of a solid. Amorphous solids usually have crystal-like arrangements of close-order molecules, i.e. not the long-range packing order of molecules found in crystalline solids. The solid state shape of a solid in a solid dispersion can be determined by polarization microscopy, X-ray powder diffraction, differential scanning calorimetry, or other methods known to those skilled in the art. The amorphous state of belinostat in solid dispersion can be identified by the characteristic broad powder x-ray pattern, while crystalline solids result in specific isolated peaks. The amorphous state can exist in two forms: one highly elastic state and one glassy state, where one state changes into another state at the glass transition temperature (Tg).

Belinostat and methods for its synthesis are described in international application WO 2002/30879. The amorphous solid dispersion may contain any pharmaceutically acceptable form of belinostat, including, without limitation, its free form and its pharmaceutically acceptable salts, solvates, or esters.

The term pharmaceutically acceptable salts refers to salts prepared with pharmaceutically acceptable, preferably non-toxic, bases or acids, including mineral or organic acids or organic or inorganic bases. Such salts are also known as acid addition salts and base addition salts. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, Pharmaceutically Acceptable Salts, J. Pharm. Sci., vol. 66, pp. 1-19.

The term solvate refers to a molecular complex comprising a drug substance and a stoichiometric or non-stoichiometric amount of one or more molecules of a pharmaceutically acceptable solvent (eg, ethanol). The term hydrate refers to a solvate comprising a drug substance and a stoichiometric or non-stoichiometric amount of water.

On the other hand, belinostat can be used in a chemically protected form. The term chemically protected form refers to a compound in which one or more reactive functional groups are protected from unwanted chemical reactions, in other words, are in the form of a protected or protecting group (also known as a masking or masking group). With respect to belinostat, the hydroxyl group may be protected as an organic or inorganic ester, for example an acetyl ether (-OC(=O)CH ₃ , -OAc) or a phosphate ester.

As used herein, the term non-ionizable (neutral) non-cellulosic polymers refers to vinyl polymers and copolymers having at least one substituent selected from the group consisting of hydroxyl, alkylacyloxy, and cycloamido; polyvinyl alcohols which have at least a portion of their repeating units in non-hydrolyzed form (vinyl acetate); copolymers of polyvinyl alcohol and polyvinyl acetate; polyvinipyrrolidone; polyoxyethylene-polyoxypropylene copolymers, also known as poloxamers; and copolymers of polyethylene and polyvinyl alcohol.

In one embodiment, non-ionizable (neutral) polymers do not include non-ionizable (neutral) cellulosic polymers such as hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose (HPMC), also called hypromellose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl cellulose; and at least partially ionizable cellulose polymers at physiologically relevant pH, such as hydroxypropyl methyl cellulose acetate succinate (HPNCAS), hydroxypropyl methyl cellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxyl methyl cellulose succinate, hydroxyethyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate (HPMCP), acetate succinate hydroxyethyl methyl cellulose, hydroxyethyl methyl cellulose acetate phthalate, carboxyethyl cellulose, carboxymethyl cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate (CAP), methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methyl cellulose acetate succinate phthalate, hydroxypropyl methyl cellulose succinate phthalate, Cellulose Phthalate Propionate, Hydroxypropyl Cellulose Butyrate Phthalate, Cellulose Acetate Trimellitate, Methylcellulose Acetate Trimellitate, Ethyl Cellulose Acetate Trimellitate, Hydroxypropyl Cellulose Acetate Trimellitate, Hydroxypro Acetate Trimellitate 3 039150 cellulose acetate, cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate pyridine dicarboxylate, cellulose acetate (salicylic acid), cellulose acetate (hydroxypropyl salicylic acid), ethylbenzoic acetate acid)cellulose, acetate (ethylphthalic acid)cellulose, acetate (ethylnicotinic acid)cellulose and acetate (ethylpicolinic acid)cellulose.

In one embodiment, the non-ionizable (neutral) non-cellulosic polymers do not include ionizable non-cellulosic polymers such as carboxylic acid-functionalized vinyl polymers and carboxylic acid-functionalized polyacrylates such as Eudragit® manufactured by Evonik; amine functionalized polyacrylates and polymethacrylates; proteins such as gelatin and albumin; and carboxylic acid functionalized starches such as starch glycolate.

In a preferred embodiment, the non-ionizable (neutral) non-cellulosic polymer is a vinyl polymer or copolymer substituted with at least one cyclic amino group (lactam) as a substituent, also referred to as a vinyl lactam polymer.

1) According to one embodiment, the present invention relates to an amorphous solid dispersion of belinostat, comprising:

a) belinostat or a pharmaceutically acceptable salt, solvate or ester thereof;

b) at least one vinyl lactam polymer; and

c) optionally at least one additive.

Preferred vinyl lactam polymers refer to polymers and copolymers comprising the following subunit:

/(CH ₂ )t

N Al (I) where m is an integer selected from 1, 2, 3 or 4 (β-, γ-, δ- or ε-lactam) and n is the number of lactam repeat units in the specified subunit, which may include from n=20 to n=30000.

According to one embodiment, said polymer is water soluble. According to one embodiment, said polymer is a linear polymer.

The term linear polymer as used herein refers to a polymer with a straight chain that consists of a long series of repeating units that are connected along said chain in a continuous fashion like chain units.

When in formula (I) m is 2 and the polymer consists of subunits (I), said vinyl lactam polymer is povidone. Povidone can also be called polyvidone, povidonum, PVP, or poly(1-vinyl-2-pyrrolidone). Commercially available povidones are typically pharmaceutical grade products with various nominal K-values characterizing their molecular weight, including

Povidone K-12 (Kollidon® 12PF, manufactured by BASF), Povidone K17 (Kollidon® 17PF, manufactured by BASF; Plasdone® C-15, manufactured by ISP), Povidone K25 (Kollidon® 25, manufactured by BASF; Plasdone® K-25, commercially available) ISP), Povidone K30 (Kollidon® 30, manufactured by BASF, Plasdone® K-29/32, manufactured by ISP), Low Peroxide Povidone K30 (Kollidon® 30 LP), Povidone K90 (Kollidon® 90F, manufactured by BASF; Plasdone® K-90, K-90 D and K-90M, sold by ISP).

The vinyl lactam polymers of the invention also include copolymers which include the above subunit (I). In particular, they include copolymers comprising a subunit (I), where M=2, and polyethylene acetate subunits of the formula

Such copolymers are called copovidone. Copovidone is a water soluble chain copolymer made from 6 parts vinylpyrrolidone and 4 parts vinyl acetate. Commercially available copovidone includes Kollidon® VA64 (manufactured by BASF), Plasdone® S-630 (manufactured by ISP). Copovidone is also called copovidonum, copovidone, copovidone or PCV-VAc copolymer (Polyvinylpyrrolidone excipients for pharmaceuticals Buhler et al 2005, Springer Verlag).

The vinyl lactam polymers of the invention also include polymers and copolymers comprising

- 4 039150 subunit (I), where m=4 (ie include caprolactam cycles).

In particular, they include Soluplus® copolymers as polyvinyl caprolactam-polyviniacet-polyethylene glycol graft copolymer, also referred to as PCL-PVAc-PEG (manufactured by BASF) of the formula

It should also be noted that the crosslinked polymers of formula (I) where m=2 are referred to as crospovidone or insoluble polyvinylpyrrolidone (Buhler et al., supra) and therefore do not refer to the linear and/or water soluble polyvinyl lactam polymers of the invention.

In a particular embodiment, said vinyl lactam polymer is selected from chain polymers and copolymers comprising the following sub-unit:

where n has the meanings given for formula (I). Examples of polymers of formula (I) are detailed below.

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Status Name Synonym Functional structure Glass transition temperature Tg Examples of excipients PVP KZO Polyvinylpyrrole (K-value 30), PV MW ~50 OOO g/mol PVP JOH, povidone R 29-32 and Water soluble, neutral (non-cellulose) Tg 156°С163°С PVP VA64 Copovidone, vinylpyrrolidone vinyl acetate, g/mol __£|-L___He___ ia M ¹ copolymer and W~45 000 Water soluble, neutral (non-cellulose) Tg 101°С one PVP/ To - Vila ? c \u003d o 1 sn, - ^J ¥ C PVPK12 Polyvinylpyrrolidone, Povidone (K-value 12), MW 2000-2500 g/mol Water soluble, neutral (non-cellulose) Tg 101°С PVP K90 Polyvinylpyrrolidone, Povidone (K-value 90), MW ~1 250 000 K g/mol Water soluble, neutral (non-cellulose) Tg 177°С potential excipients, PVPK17 polyvinylpyrrolidone, povidone water soluble, Tg 136°С

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suitable for improving the spray-dried amorphous dispersion (K-value 17), MW 9000-10,000 g/mol neutral (non-cellulose) PVPK25 Polyvinylpyrrolidone, Povidone (K-value 25), MW 25,000-30,000 g/mol Water soluble, neutral (non-cellulose) Tg 152°С Soluplus® BUT on O τ but Graft copolymer polyvinyl caprolactam polyvinyl acetate polyethylene glycol, PEG 6000/vinyl caprolactam/vinylacetate 13/57/30 MW - 118,000 g/mol Water soluble, neutral (non-cellulose) Tg 70°C

In particular, vinyl lactam polymers are selected from povidone polymers and copovidone copolymers, in particular Soluplus®, PVP, such as PVP K30, PVP K12, PVP K17, PVP K25, PVP K90 and PVP VA64, and any of their mixtures, such as mixture 20 /80, 30/70, 40/60, 50/50, 60/40, 70/30 or 80/20 PVP K30/PVP VA64, PVP K30/Soluplus, PVP K30/PVP K90.

More specifically, the vinyl lactam polymers are selected from PVP K30, PVP K12 and PVP VA64 and mixtures thereof, especially PVP K30 and PVP VA64 and mixtures thereof.

In one embodiment, the non-ionizable (neutral) non-cellulosic polymer is a polyvinyl alcohol (PVA) polymer.

In a separate embodiment, the PVA polymer is polyvinyl alcohol. In another embodiment, the PVA polymer is a polyvinyl alcohol-polyethylene glycol graft copolymer called Kollicoat® IR. Kollicoat® IR polymer consists of approximately 75% polyvinyl alcohol units and approximately 25% polyethylene glycol units.

According to one embodiment, the amorphous solid dispersion of belinostat may also include at least one additive.

According to one embodiment, said additive may be selected from common excipients that are commonly used in oral formulations and/or solid dispersions. Suitable additives include, in particular, antioxidants, dispersants, pH modifiers, solubilizers, stabilizers, disintegrators, or any mixture thereof.

pH modifiers such as acids, alkalis, or buffers may be used to reduce hydrolysis and/or chemical degradation, but may also alter the rate of dissolution; they include, in particular, KOH, NaOH, CaCO ₃ , L-arginine, meglumine, Na carbonate, Na bicarbonate, citric acid or succinic acid, etc.

Antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulphite (SMB), propyl gallate (PG), ascorbyl palmitate, dihydroxybenzoic acid, cysteine, ascorbic acid, alphatocopherol (Vit-E), etc., in particular.

Suitable solubilizers are additives that can improve the in vitro dissolution profile (higher supersaturation) and wettability, but they can also inhibit crystallization. Solubilizers can be anionic, cationic, amphoteric or nonionic surfactants. These include, in particular, polysorbate (e.g. Tween 80), sodium lauryl sulfate (SLS), lauryl polyoxyl-32 glycerides (Gelucire

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44/14), D-a-tocopherol (polyethylene glycol 1000) succinate (TPGS), poloxamers (e.g. Pluronic

F127). Solubilizers may also include cyclodextrins such as β-cyclodextrin sulfobutyl ether or hydroxypropyl-v-cyclodextrin.

When such additives are included as part of the dispersion itself, they can make up to 25% of the dispersion.

Stabilizers are additives that can improve chemical and/or physical stability. Stabilizers include, in particular, amino acids (eg L-histidine, L-lysine, L-leucine, L-arginine, glycine, phenylalanine, tryptophan and tyrosine) or sugars (eg sorbitol, glycerol, mannitol, xylitol, sucrose, trehalose).

When such additives are included as part of the dispersion itself, they can make up to 25% of the dispersion.

According to one embodiment, the amorphous solid dispersion may include about 5-80% by weight of belinostat; and about 20-95% by weight of said non-ionizable non-cellulosic polymer such as vinyl lactam polymer;

in particular, about 15-50 wt.% belinostat and about 50-85 wt.% of the specified non-ionizable non-cellulosic polymer, such as a polymer of vinyl lactam.

The amorphous solid dispersion is physically stable in the sense that the belinostat can retain its substantially amorphous form in the formulation after storage for at least 2 years. In order to reduce the risk of crystallization and ensure long-term stability, the ASD of the belinostat according to the invention can also be stored in a water vapor protected package to prevent absorption of water by the dispersion.

It has also been found that the amorphous solid dispersions of the invention are chemically stable. Due to their hydroxyl group, belinostat in solution, as well as belinostat in the amorphous state, has been found to be highly resistant to hydrolysis and chemical degradation, like other hydroxamic acid-based HDAC inhibitors. In the amorphous state, the main impurities in belinostat are belinostat acid and belinostat dimer.

Belinostat acid ((E)-3-[3-(phenylsulfamoyl)phenyl]prop-2-enoic acid) has the formula

It is an intermediate in the synthesis of the drug substance belinostat, a decomposition product of belinostat upon hydrolysis of the hydroxymeric acid functionality, and also a metabolite (Finn et al., 2016).

Belinostat dimer ((E)-3 -(3 -(N-phenylsulfamoyl)phenyl)-N-(((E)-3 -(3 -(N-phenylsulfamoyl)phenyl)acryloyl)oxy)acrylamide) has the formula

It is formed as a result of the decomposition of belinostat due to the loss of hydroxamine. It is also an impurity in the synthesis of the drug substance belinostat, which is removed during the manufacturing process by recrystallization.

When solid dispersions are prepared using ionizable or neutral cellulosic polymers or ionizable non-cellulosic polymers, significant chemical degradation to belinostat acid or belinostat dimer can be observed upon storage.

Surprisingly, when using non-cellulosic neutral polymers such as vinyl lactam polymers, the amorphous solid dispersion obtained according to the invention is chemically stable, while the decomposition of belinostat into its two main impurities in the amorphous solid dispersion preparation is kept within the following limits:

less than 0.2% belinostat acid and/or belinostat dimer as tested at the end of production; and/or less than 2% belinostat acid and/or belinostat dimer after storage for at least 18 months, preferably at least 24 months, most preferably at least 36 months, under ICH (International Council for the Harmonization of Technical Specifications) storage conditions. requirements for pharmaceutical preparations for human use).

The amorphous solid dispersions of the invention provide improved solubility and dissolution characteristics as compared to the crystalline drug substance when tested in in vitro dissolution tests.

In some embodiments, the compositions, when tested in an in vitro test at a 5-fold supersaturation level, show an increase in the solubility of belinostat in 90 minutes by at least

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1.5 times compared to the non-dispersed crystalline drug, when tested under the same conditions, typically at least 2 times or even at least 2.5 times.

Given the exceptionally low water solubility of belinostat, such a significant increase in solubility when using the dispersions according to the invention is quite unexpected.

Within the scope of the invention, amorphous solid dispersions providing improved in vitro solubility properties also significantly improve plasma exposure and in vivo bioavailability.

When tested in vivo, a composition of the invention exhibits either a _Cmax or AUC that is at least 1.25 times greater than the corresponding _Cmax or AUC exhibited by a composition comprising the same amount of undispersed crystalline drug substance. Preferably Cmax or AUC is at least 1.5 times greater, more preferably 2 times greater.

It can also be said that such compositions have a relative bioavailability of at least about 1.25 times higher compared to the non-dispersed crystalline drug substance, usually to a level of at least 2 times higher.

According to the second objective, the present invention also relates to a method for producing an amorphous solid dispersion according to the invention.

An amorphous solid dispersion can be obtained by any of the methods known in the art, including spray drying, melt extrusion (HME) and precipitation from solution with the addition of a non-solvent. Preferably, this method is a spray drying method.

According to one embodiment, said method comprises the steps of providing a solution of belinostat and said non-ionizable non-cellulosic polymer, such as vinyl lactam polymer, in a solvent, optionally with said optional additives; and spray drying said solution.

Spray drying is a process that is generally well known in the art and typically involves transforming a solution into a dry form by spraying the solution into a hot drying medium. The spray-dried product is usually in the form of a powder consisting of individual particles or agglomerates, depending on the physical and chemical properties of the preparation and the design of the dryer and operation. The basic method usually includes the following four steps: a) spraying the solution; b) spray-gas contact; c) drying the spray; and d) separating the dry product from the drying gas.

Modern spray drying typically involves atomizing the solution (raw material) as a spray of droplets and contacting these droplets with a hot gas in a drying chamber. Drops can be obtained using, for example, spray nozzles. Evaporation of moisture from the resulting droplets and the formation of dry particles can proceed under conditions of controlled temperature and gas flow. When the droplets are small enough and the chamber is large enough, the droplets usually dry out before reaching the walls of the chamber. The resulting product is collected as a free flowing material. The powder can be discharged from the drying chamber continuously. The operating conditions and design of the spray dryer are generally selected according to the drying characteristics of the product and the description of the powder.

Spray dryers typically include a raw material pump, sprayer, gas preheater, drying chamber, and exhaust gas purification and powder recovery systems. An example of a spray drying system includes a drying gas fed to a pre-filter. In one embodiment, the drying gas is nitrogen and the presence of oxygen is avoided. The drying gas then passes through a fan and a heater, which may be an electric heater. The drying gas then passes through thermometer monitors to measure the temperature of the gas at the inlet before it enters the drying chamber through the gas distributor at the top. Double filtration can be used to guarantee the quality of the product.

The solvent is usually selected from organic solvents which can dissolve both the belinostat and the non-ionizable polymer such as the vinyl lactam polymer. Suitable solvents include methanol, acetone, chloroform, ethanol, dichloromethane, water. Typically, 5-50% solids solutions are obtained.

According to another embodiment, said method comprises the steps of mixing belinostat and said non-ionizable, non-cellulosic polymer, such as vinyl lactam polymer, finally with optional additives; and extruding the mixture using a temperature controlled extruder. In any embodiment of the method, amounts of belinostat and polymer are usually used in the appropriate ratio desired for an amorphous solid dispersion, as discussed above.

The amorphous solid dispersion of the invention is suitable for oral administration of belinostat.

According to a third object, the present invention relates to a pharmaceutical composition comprising an amorphous solid dispersion of a belinostat according to the invention, optionally with one or more pharmaceutically acceptable excipients.

The compositions are conveniently prepared by any of the methods known in the pharmaceutical art, for example as described in Remington: The Science and Practice of Pharmacy, 20th ed.; Gennaro A.R., Ed.; Lippincott

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Williams & Wilkins: Philadelphia, PA, 2000.

Formulations suitable for oral administration to a patient include discrete units such as capsules, soft or hard gelatin capsules, tablets, each containing a predetermined amount of belinostat and/or belinostat amorphous solid dispersion. They also include powders or granules; multiparticulates, suspensions in an aqueous liquid or in a non-aqueous liquid. Pharmaceutical compositions may optionally be coated.

The terms pharmaceutical or pharmaceutically acceptable refer to molecules and compositions that do not cause an adverse, allergic or other undesirable reaction when administered, as appropriate, to an animal or human.

Used in the present description, the term pharmaceutically acceptable excipient includes, in particular, diluents, adjuvants, carriers or media. The use of such ingredients for pharmaceutically active substances is well known in the art.

The amorphous solid dispersion of belinostat can be administered in unit dose form, where the term unit dose means a single dose that can be administered to a patient and is ready for use and packaged.

The daily dose according to the invention can be achieved by administering half of the unit dosage form, one unit dosage form, two or more unit dosage forms, according to the unit dosage form available on the market, the daily dose to be administered and the frequency of administration as prescribed by the physician.

According to another object, the present invention also relates to an amorphous solid dispersion of a belinostat according to the invention for use in the treatment and/or prevention of cancer.

Used in the present description, the term cancer refers to various forms of malignant neoplasms, including tumors or leukemia. In the present description, this term covers malignant neoplasms of the breast, prostate, lung, colon, bladder, brain, stomach, kidneys, liver, ovaries, mouth, skin, intestines, uterus, head and neck, larynx, hematopoietic and lymphoid tissues and blood. In particular, lymphoma is provided, ie. blood cell cancers, including Hodgkin's lymphomas, non-Hodgkin's lymphomas and multiple myeloma, and more particularly recurrent or resistant peripheral T-cell lymphoma (PTCL).

Identification of subjects who are in need of treatment for the diseases and conditions described herein is well within the ability and knowledge of a person skilled in the art. A practitioner in the art, using clinical tests, physical examination, genetic tests, and medical history/family history, can readily identify those subjects in need of such treatment.

Actual dosage levels of the belinostat solid dispersion of the invention may vary so as to obtain an amount of active ingredient that is effective to produce the desired therapeutic response to a given composition and route of administration. Therefore, the selected dosage level depends on the desired therapeutic effect, the route of administration, the desired duration of treatment and other factors, such as the condition of the patient.

A therapeutically effective amount can easily be determined by a physician of ordinary skill in the art using conventional methods and observing results obtained under similar circumstances. In determining a therapeutically effective amount, the clinician will consider a number of factors, including, but not limited to, the subject's species, size, age, and general health, their particular disease, the degree of injury or severity of disease, the individual subject's response, the particular compound being administered, the route of administration, the bioavailability property of the administered drug, the selected treatment regimen, the use of concomitant drug treatment and other relevant circumstances.

The amount of amorphous solid dispersion required to achieve the desired biological effect will vary depending on a number of factors, including the dose of drug administered, the type and progression of the disease, the disease state of the patient, and the route of administration.

In the context of the invention, the term treatment as used herein means the reversal, alleviation, suppression of development or prevention of the disorder or condition to which such a term is applied, or one or more symptoms of such a disorder or condition.

A therapeutically effective amount means an amount of a compound/pharmaceutical composition of the present invention effective to produce the desired therapeutic effect.

According to the invention, the term patient or patient in need thereof is intended to refer to a human or non-human mammal affected or possibly affected by the above disorders. Preferably the patient is a human.

Blueprints

The figure illustrates the results of the comparison of pharmacokinetics in dogs from example 5.

The following examples are given as an explanation of the invention.

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Examples

Example 1 Bioavailability of oral solid dosage form of belinostat.

A PK study was performed in dogs to compare plasma drug concentrations and bioavailability of 5 different oral solid dosage forms of belinostat. Formulations A, B, C, D, and E (compositions are shown in Table 1) were administered by oral gavage to 5 fasted female beagle dogs (7.09.0 kg) at a fixed dose of 50 mg per dog (equivalent to 6.5 -10.2 mg/kg). Each formulation was given to the animals once with a washout period of one week between each dosing. Performed intravenous dosing to calculate the absolute bioavailability by slow bolus injection into the cephalic vein.

After each dose, blood samples are taken from the saphenous or cephalic veins into heparinized tubes at the following time points: 5, 15 and 30 minutes, 1, 3, 6, 12, 24 and 36 hours. Plasma belinostat concentration is measured using a validated bioanalytical method ( solid phase extraction, UHPLC-MS/MS, concentration range 2-2000 ng/ml).

Pharmacokinetic parameters are obtained from individual plasma concentration profiles using a compartment-independent analysis using WinNonlin Professional (version 4.1).

_Cmax , AUC _0-24 and bioavailability (F%), calculated for each dog and then averaged for the test population, are given in table. one.

Table 1. Pharmacokinetic parameters of various oral dosage forms of belinostat in dogs

Dose IV Preparation with arginine Preparation A Pure belinostat in capsule Drug B Prototype tablet Preparation C Suspension in capsule Preparation D Granulate in capsule I Preparation E Granulate in capsule II Dosing way. IV Peror. Peror. Peror. Peror. Peror. Composition Belinostat solution 50 mg/ml, containing. 10% Larginine in SWFI 50 mg, non-microniz. belinostat capsule 50 mg tablets (55.56% micronized belinostat, 16% pregelatin, starch, 16.24% microcrysts, cellulose, 2.2% povidone, 6% Capsules 50 mg (10% micronized belinostat in suspension in liquid lipid medium: 80% Capsules 50 mg (83% microniz. Belinostat, 4.5% Povidone K12, 2.5% SLS, 10% 50 mg capsules (60% micronized belinostat, 37% maltodextrin, 3% SLS) crospovidone, 3% SLS, 0.25% colloidal silicon dioxide, 0.75% magnesium stearate) Miglyol 812N and 10% lecithin) poloxamer a 188) Stax (ng/ml) 5830 183 309 154 176 218 AUC 0-24 (ng*h/ml) 2700 428 429 396 345 323 Bioavailability 100% 15.9% 15.9% 14.7% 12.8% 12.0%

All oral forms of administration lead to similar levels of drug concentrations, with AUC _0-24 ranging from 12 to 16% of the intravenous dosage. Various types of oral administration do not change the concentration profile and do not increase bioavailability compared to pure belinostat in capsules.

The results show that neither conventional capsules (preparation A), nor micronized belinostat in tablets/capsules (preparations B, D and E) or formulations in liquid lipid suspension (preparation C) are suitable in terms of improving the bioavailability of belinostat compared to crystalline form, and confirms the need for a specific technology that provides the ability to improve solubility and thus bioavailability.

Example 2 Amorphous solid dispersion.

Various belinostat and polymer ASDs were obtained by spray drying according to the following procedure.

Belinostat solutions are prepared with various polymers (selected from HPMCAS-L, HPMCAS-M, HPMCAS-H, HPMC E3, PVP K12, PVP K30, PVP VA 64, Eudragit L100, Eudragit E PO, Eudragit S100, HPMCP HP 55S, CAP and PVP K30/PVP K90) in methanol, methanol/water, or acetone (3-10 wt.% solids in solvent) and spray dried using a Bend Research Custom Built Lab Scale Spray Dryer [Bend Research, Bend OR , Equipment ID# B RI-EQ-0036], and give fine particles of a spray-dried solid dispersion on a scale _of 7.5-10 g. and ASD with PVP K30 are tested with antioxidant [BHT] or stabilizers [L- 11 039150 histidine]. Also check the mixture of PVP K30 and PVP K90 in relation to 75/25. When an additive is used, it is dissolved and mixed with belinostat and polymer before spray drying. The following conditions were used for all experiments: spray pressure ~ ^689.5-965.3 kPa (100-140 psi), gas flow rate 450-475 g/min, solution flow rate 10-30 g/min, temperature at the inlet 81-166°C.

After secondary drying overnight at 40°C, 15% RH, in a convection tray dryer, the various ASDs were characterized by physical stability (XRPD, Tg vs. relative humidity), chemical stability (for impurities by HPLC after 1 week at 40°C/75 % RH) and dissolution in vitro.

Get different drugs and experience, which is summarized below in table. 2. If in the table. 2 does not state otherwise, ASDs contain 25% belinostat. Some formulations are tested with a drug loading of 15-50%. Theoretically, a higher or lower drug loading can be imagined.

Example 3 Physical stability.

The amorphous or crystalline state of the freshly obtained spray-dried dispersions described in Example 2 was evaluated by powder X-ray diffraction (XRPD). The same analysis is repeated after 1 week of storage at 40° C. and 75% relative humidity when uncovered.

X-ray patterns are obtained using a Rigaku MiniFlex 600 X-ray diffractometer operating with a copper anode (Κ _α1 = 1.5060 A; Κ _α2 = 1.54439 A), set the generator to 45 kV and 15 mA, in the range 2-θ 3-40 ° 2θ, scanning at 2.5° 2θ per minute in continuous mode, and using a high speed D/teX Ultra detector.

In table. 2 describes the crystalline/amorphous state of various ASDs made with belinostat. The diffractograms of all ASDs show a wide amorphous halo in the absence of sharp signals as a typical example. The disappearance of the belinostat crystal peaks in the spray-dried samples indicates that the various spray-dried dispersions are essentially amorphous. On the contrary, amorphous belinostat, unstabilized by the polymer, undergoes recrystallization during storage.

After 1 week storage at 40°C and 75% relative humidity (open), with the exception of spray-dried belinostat (no polymer), all spray-dried dispersions were essentially amorphous. They show the overall good physical stability of belinostat in amorphous form dispersed in various polymers.

Also, to assess the physical stability of the obtained ASD determine the glass transition temperature (Tg) by the method of modified differential scanning calorimetry (m-DSC) in two conditions of relative humidity (RH) (<5% and 75% RH).

DSC curves were recorded using TA instruments on a Q2000 differential scanning calorimeter. Samples are heated in a stream of nitrogen from 0 to 200°C at a rate of 2.5°C ± 1.5°C/min in a leaky closed boat for analysis at <5% RH or from 0 to 130°C at 2.5°C ±1.5°C/80 s in a sealed assay boat at 75% RH.

In table. 2 describes the Tg of various ASDs obtained with belinostat.

Amorphous belinostat has a relatively low glass transition temperature (Tg), which is approximately 53°C. Since the molecules, even in a glassy amorphous state, have some mobility, it is known in the art that it is advantageous when the ASD glass transition temperature is higher than the actual storage temperature (at least above 20°C and preferably above at least 40°C).

Comparing all recorded Tg values of spray-dried amorphous dispersions with PVP K12, PVP K30, PVP VA 64, they were found to have satisfactory glass transition temperatures (>100°C at <5% RH%).

Thus, ASDs of belinostat with vinyl lactome polymers show good physical stability in the amorphous state.

Example 4 Chemical Stability

Due to the hydroxamide functionality, belinostat is readily hydrolyzed, so the development of a chemically stable ASD is required.

The purity of each batch of ASD is verified by HPLC analysis of the sample upon receipt and after one week of storage under accelerated stability test conditions: 40°C/75% RH open or closed. When closed, the ASDs are placed in resealable vials (heat-closed) containing 1 g of SORB-IT desiccant per container.

HPLC analysis is performed using an Agilent 1100 or 1200 system with a dual or quad pump, diode array detector, cooled autosampler, and column oven. The assay data is obtained using the Empower 3 software. The column used is a Zorbax Bonus RP, 4.6 x 150 mm (3.5 µm) column. As the mobile phase, a mixture of acetonitrile/10 mM potassium phosphate buffer, pH 3.0, with a gradient

- 12 039150 concentration at a flow rate of 1.0 ml/min; UV detection is used at a wavelength of 220 nm.

Belinostat leads to two main impurities: belinostat acid (Bel acid) and belinostat dimer (Bel dimer).

In table. 2 shows the purity profiles of each spray-dried dispersion showing area % of all impurities and area % of belinostat acid (Bel acid) and belinostat dimer (Bel dimer) impurities.

For most ASDs, the dimer impurity content and all impurity values are initially low, but the level of impurities increases substantially with time of storage under accelerated stability test conditions. Variations in the formation of impurities, especially dimer impurities, are observed depending on the associated polymer.

Cellulose-based ASDs (HPMCAS, HPMC, HPMCP, CAP) (preparations 3-12) show rapid chemical degradation. To overcome possible acid-catalyzed hydrolysis of hydroxamide at the expense of the acidic function of the HPMCAS-M polymer, pH modifier additions were tested (preparations 5 and 6). This results in more chemical degradation, so this approach has not been satisfactory either. Other polymers (ionizable non-cellulose) such as Eudragit® (preparations 23-25) were also unsatisfactory as they led to increased chemical degradation.

However, the results show that only non-ionizable (neutral) non-cellulose polymers such as vinyl lactam polymers (such as PVP VA64, PVP K12 and one PVP K30 mixed with PVP K90 or with an additive such as a stabilizer) can significantly prevent/reduce dimer formation. unlike other polymers (preparations 13-22).

Example 5 Dissolution without runoff in vitro.

In vitro dissolution of spray-dried belinostat materials is tested under non-sink conditions to evaluate the ability of formulations to achieve supersaturation and substantially supersaturation relative to the crystalline drug substance.

Dissolution is assessed using the microcentrifuge dissolution method (Curatolo et al., Pharm. Res., 2009, 26(6): 1419-1431). The microcentrifuge dissolution method consists of injecting 1.8 mg equivalent of belinostat as ASD into an empty microcentrifuge tube and adding only 1.8 ml of dissolution medium (PBS, pH 6.5, with 0.5 wt. ) to achieve the theoretical maximum concentration of belinostat in solution of 1000 µg/ml. For some formulations (marked * in Table 2), ASD was first exposed to the gastric environment, pH 2.0, at 2000 μg/ml for 30 min before being transferred to PBS, pH 6.5, with 0.5 wt.% liquid , which simulates the liquid in the intestine, at a theoretical maximum concentration of belinostat in solution of 1000 µg/ml. The tubes were placed at 37°C. Aliquots (50 µl) were taken from the supernatant after centrifugation at 15800 g for 1 min at each time point (5, 10, 20, 45, 90 and 1200 min). Between the indicated times, the solids in the centrifuge tube were resuspended by continuously mixing the sample in a vortex mixer for 30 seconds and the tube was again placed at 37°C. Aliquot samples were diluted with acetonitrile and drug concentration was determined by HPLC.

In table. 2 shows C _{90 min} and C ₁₂₀₀ min which are the concentrations in the dissolution medium obtained after 90 and 1200 min.

When using the ASD according to the invention, the concentration of belinostat in solution after 90 minutes is 2-3.5 times higher compared to the concentration of the non-dispersed drug substance. Similar solubility values are obtained after 1200 minutes, which indicate the ability of the selected polymers to maintain the supersaturation level over time.

- 13 039150

Table 2 Summary of Physical Stability, Chemical Stability, and Dissolution Results of Different Amorphous Solid Dispersions with Belinostat (ASD)

Compound Physical stability Chemical stability (area of impurities, %) Dissolution Tg (°C) <5%RH ^a Tg (°C) 75%RH ^b Initial XRPD XRPD, 1 week 40/75, open Initial 1 week 40/75 open 1 week 40/75 closed Dissolution SeOmin, mcg/ml Dissolution CgOh, mcg/ml controls one Crystal. NA NA Crystal. Crystal. Bel-acid <0.05 Bel-dimer NA All approx. <0.05 / 270 310 2 Dried, sprayed, belinostat 53 He found Partial crystal. Crystal. Bel-acid 0.05 Bel-dimer 0.48 All approx. 0.59 Bel-acid 0.10 Bel-dimer 0.25 All approx. 0.42 See the recrystal. Bel-acid 0.10 Bel-dimer 1.34 All approx. 1.49 363 A recrystal is observed. 387 ASD based on cellulose polymers (non-ionizable and ionizable) 3 HPMCAS-L 81 37 Amorphous Amorphous Bel-acid ND Vedimer 0.19 All approx. 0.45 Bel-acid 0.14 Bel-dimer 2.07 All approx. 2.44 Didn't fulfill 980 920 four HPMCAS-M 83 38 Amorphous Amorphous Bel-acid ND Bel-dimer 0.20 All approx. 0.39 Bel-acid 0.10 Bel-dimer 1.77 All approx. 2.11 Didn't fulfill 950 920 5 HPMCAS-M+ Sheq.KOH 87 37 Amorphous Amorphous Bel acid ND Bel dimer 0.09 Total approx. 1.95 Be-acid 2.86 Bel-dimer 2.21 All approx. 8.80 Bel-acid 0.19 Bel-dimer 0.32 All approx. 2.12 785 770 6 HPMCAS-M + 2% CaCO3 80 33 Amorphous Amorphous Bel-acid 0.09 Bel-dimer 0.99 All approx. 1.72 Bel-acid 0.17 Bel-dimer 1.85 All approx. 2.81 Bel-acid 0.09 Bel-dimer 1.23 All approx. 2.12 896 883 7 HPMCAS-M (50% API) 71 42 Amorphous Amorphous Bel-acid ND Bel-dimer 0.17 All approx. 0.45 Bel-acid 0.13 Bel-dimer 1.76 All approx. 1.98 Bel-acid ND Bel-dimer 0.71 All approx. 0.81 922 909 eight HPMCAS-M (75% API) 60 27 Amorphous Amorphous Bel-acid ND Bel-dimer 0.21 All approx. 0.59 Bel-acid 0.22 Bel-dimer 1.88 All approx. 2.40 Bel-acid 0.08 Bel-dimer 0.87 All approx. 1.14 774 789 9 HPMCAS-H 80 42 Amorphous Amorphous Bel-acid 0.04 Bel-dimer 0.18 All approx. 0.28 Bel-acid 0.16 Bel-dimer 1.37 All approx. 1.69 Bel-acid 0.07 Bel-dimer 0.83 All approx. 0.95 602 596 ten NRMS EZ 93 thirty Amorphous Amorphous Bel-acid ND Bel-dimer 0.10 All approx. 0.30 Bel-acid 0.19 Bel-dimer 0.62 All approx. 1.18 Didn't fulfill 700 780 eleven HPMCP HP55S too 46 Amorphous Amorphous Bel-acid 0.04 Bel-imer 0.17 Bel-acid 0.38 Bel-dimer 1.53 Bel-acid 0.06 Bel-dimer 0.84 751 759 All approx. 0.27 All approx. 1.96 All approx. 0.94 12 cap 110 46 Amorphous Amorphous Bel-acid 0.03 Bel-dimer 0.22 All approx. 0.31 Bel-acid 0.27 Bel-dimer 2.14 All approx. 2.46 Bel-acid 0.06 Bel-dimer 0.68 All approx. 0.78 723 715 ______________________ASD based on non-ionizable (neutral) non-cellulose polymers 13 PVP K30 (15% API) 146 thirty Amorphous Amorphous Bel-acid 0.04 Bel-dimer 0.03 All approx. 0.24 Bel-acid 0.14 Bel-dimer 0.18 All approx. 0.56 Bel-acid 0.05 Bel-dimer 0.04 All approx. 0.31 965 1020 fourteen PVP K30 (25% API) 139 43 Amorphous Amorphous Bel-acid 0.04 Bel-dimer 0.05 All approx. 0.15 Bel-acid 0.14 Bel-dimer 0.30 All approx. 0.52 Bel-acid 0.05 Bel-dimer 0.13 All approx. 0.24 806 837 fifteen PVP K30 (50% API) 107 49 Amorphous Amorphous Bel-acid 0.04 Bel-dimer 0.04 All approx. 0.26 Bel-acid 0.10 Bel-dimer 0.46 All approx. 0.83 Bel-acid 0.05 Bel-dimer 0.18 All approx. 0.44 813 809 16 PVP K30, low peroxide 140 39 Amorphous Amorphous Bel-acid 0.03 Bel-dimer 0.03 All approx. 0.27 Bel-acid 0.09 Bel-dimer 0.20 All approx. 0.55 Bel-acid 0.05 Bel-dimer 0.06 All approx. 0.33 933 975 17 PVP K30 + 2%BHT 135 41 Amorphous Amorphous Bel-acid 0.03 Bel-dimer 0.03 All approx. 0.24 Bel-acid 0.11 Bel-dimer 0.20 All approx. 0.56 Bel-acid 0.05 Bel-dimer 0.05 All approx. 0.29 960 1006 eighteen PVPK30 + ₂ %NaHCO3 141 38 Amorphous Amorphous Bel-acid 0.07 Bel-dimer 0.03 All approx. 0.32 Bel-acid 0.26 Bel-dimer 0.15 All approx. 0.85 Bel-acid 0.11 Bel-dimer 0.03 All approx. 0.47 1000 979 19 PVP VA64 108 36 Amorphous Amorphous Bel-acid ND Bel-dimer 0.04 All approx. 0.20 Bel acid 0.07 Bel dimer 0.31 Total approx. 0.58 Didn't fulfill 530 570 twenty PVPK12 too 0 Amorphous Amorphous Bel-acid <0.05 Bel-dimer <0.05 All approx. 0.11 Bel-acid 0.06 Bel-dimer 0.21 All approx. 0.33 Bel acid <0.05 Bel dimer 0.10 Total approx. 0.24 597* 714* 21 PVP K30+ 5%L- histidine 121 33 Amorphous Amorphous Bel-acid <0.05 Bel-dimer <0.05 All approx. 0.06 Bel-acid 0.07 Bel-dimer 0.17 All approx. 0.33 Bel-acid 0.06 Bel-dimer 0.12 All approx. 0.25 788* 815* 22 PVP K30/PVP K90 131 24 Amorphous Amorphous Bel-acid <0.05 Bel-dimer 0.09 All approx. 0.15 Bel acid 0.06 Bel dimer 0.31 Total approx. 0.44 Bel-acid 0.05 Bel-dimer 0.18 All approx. 0.31 577* 727* _________ ASD based on ionizable non-cellulose polymers 23 Eudragit L100 151 Phase separation Amorphous Amorphous Bel acid ND Bel dimer 0.22 Total approx. 0.86 Bel-acid 0.44 Bel-dimer 1.33 All approx. 1.93 Didn't fulfill 960 940 24 Eudragit E PO 62 33 Amorphous Amorphous Bel-acid ND Bel-dimer 0.06 All approx. 0.74 Bel-acid 0.79 Bel-dimer 0.29 All approx. 1.84 Bel-acid 0.13 Bel-dimer 0.23 All approx. 0.83 173 211 25 Eudragit S100 Can't be determined Can't be defined Amorphous Amorphous Bel-acid 0.05 Bel-dimer 0.26 All approx. 0.37 Bel-acid 0.54 Bel-dimer 1.08 All approx. 1.67 Bel-acid 0.10 Bel-dimer 0.75 All approx. 0.89 921 876

ND: not defined.

*preparations in which in vitro dissolution was first carried out at pH 2.0 of the gastric medium for 30 minutes before dilution in PBS medium, pH6.5.

Conclusions.

Regarding chemical stability: The formation of dimer impurity varies depending on the polymers used.

In vitro dissolution data of various amorphous spray-dried dispersions of belinostat of the invention with a non-ionizable (neutral) non-cellulosic polymer such as vinyl lactam polymer show significantly higher solubilities compared to non-dispersed crystalline belinostat and show that these dispersions markedly increase the dissolution rate of the drug substance. .

It turns out that polymers belonging to the group of polymers of vinyl lactams provide good chemical stability of belinostat in the amorphous state. Other vinyl lactam polymers such as Soluplus®, other molecular weight PVP (PVP K17, PVP K25) are also expected to be suitable polymers.

The above results show that only polymers of the polyvinyl lactam class lead to outstanding chemical stability together with a suitable Tg, good physical stability and a satisfactory dissolution profile.

Surprisingly, polyvinyl lactam polymers have been found to achieve satisfactory dissolution as well as low levels of dimer formation.

Three ASDs are also tested for stability over a longer period (1, 3 and 6 months at 5°C and real time (25/60 open and closed) and stability under accelerated test conditions (30/65 closed) ( see table 3 below).

Table 3. 6 month retention of ASD chemical stability with PVP VA64, PVP K30 and HPMCAS-M

Chemical stability (area of impurities, %) 25°C, 60% RH, closed (dryer) 25°C, 60% RH, open 30°C, 65% RH, closed (dryer) Refrigerator 2-8°С (open) weeks PVP VA 64 0 Be1-acid 0.05 Be1-dimer 0.06 All approx. 0.16 Bel-acid 0.05 Be1-dimer 0.06 All approx. 0.16 Bel-acid 0.05 Be1-dimer 0.06 All approx. 0.16 Bel-acid 0.05 Be1-dimer 0.06 All approx. 0.16 four Be1-acid <0.05 Be1-dimer 0.10 All approx. 0.20 Bel-acid <0.05 Be1-dimer 0.12 All approx. 0.22 Bel-acid 0.04 Be1-dimer 0.11 All approx. 0.21 Bel-acid 0.03 Be1-dimer 0.04 All approx. 0.12 12 Be1-acid 0.06 Be1-dimer 0.16 All approx. 0.26 Bel-acid 0.07 Be1-dimer 0.22 All approx. 0.33 Bel-acid 0.07 Be1-dimer 0.21 All approx. 0.33 Bel-acid, not tested. Bel-dimer, not tested. All comments, not tested. 24 Be1-acid 0.05 Be1-dimer 0.23 All approx. 0.44 Bel-acid 0.12 Be1-dimer 0.34 All approx. 0.63 Bel-acid 0.07 Be1-dimer 0.37 All approx. 0.62 Bel-acid 0.4 Be1-dimer 0.06 All approx. 0.35 weeks HPMCAS-M 0 Bel-acid 0.04 Be1-dimer 0.22 All approx. 0.31 Bel-acid 0.04 Be1-dimer 0.22 All approx. 0.31 Bel-acid 0.04 Be1-dimer 0.22 All approx. 0.31 Bel-acid 0.04 Be1-dimer 0.22 All approx. 0.31 four Bel-acid 0.05 Be1-dimer 0.59 All approx. 0.69 Bel-acid 0.08 Be1-dimer 0.84 All approx. 0.98 Bel-acid 0.03 Be1-dimer 0.74 All approx. 0.83 Bel-acid 0.04 Be1-dimer 0.27 All approx. 0.36 12 Bel-acid 0.07 Be1-dimer 0.88 All approx. 1.00 Bel-acid 0.14 Be1-dimer 1.48 All approx. 1.69 Bel-acid 0.09 Be1-dimer 1.28 All approx. 1.42 Bel-acid, not tested. Bel-dimer, not tested. All comments, not tested. 24 Bel-acid 0.08 Be1-dimer 1.48 All approx. 1.65 Bel-acid 0.33 Be1-dimer 2.69 All approx. 3.14 Bel-acid 0.16 Be1-dimer 2.58 All approx. 2.85 Bel-acid 0.05 Bel-dimer 0.36 All approx. 0.53 weeks PVPK30 0 Bel-acid 0.04 Be1-dimer 0.05 All approx. 0.15 Bel-acid 0.04 Be1-dimer 0.05 All approx. 0.15 Bel-acid 0.04 Be1-dimer 0.05 All approx. 0.15 Bel-acid 0.04 Bel-dimer 0.05 All approx. 0.15 four Bel-acid 0.04 Be1-dimer 0.08 All approx. 0.18 Bel-acid 0.07 Be1-dimer 0.13 All approx. 0.27 Bel-acid 0.04 Be1-dimer 0.12 All approx. 0.23 Bel-acid 0.03 Bel-dimer 0.03 All approx. 0.12 12 Bel-acid 0.05 Be1-dimer 0.15 All approx. 0.38 Bel-acid 0.09 Be1-dimer 0.18 All approx. 0.48 Bel-acid 0.07 Be1-dimer 0.22 All approx. 0.50 Bel-acid 0.04 Bel-dimer 0.04 All approx. 0.26 24 Bel-acid 0.07 Be1-dimer 0.25 All approx. 0.47 Bel-acid 0.17 Be1-dimer 0.28 All approx. 0.65 Bel-acid 0.12 Be1-dimer 0.44 All approx. 0.73 Bel-acid 0.04 Bel-dimer 0.06 All approx. 0.31

These results show that belinostat ASDs with polymers of the polyvinyl lactam class show outstanding chemical and physical stability even during long-term storage, and that no crystallization is observed when analyzed by XRPD.

Example 6 In vivo activity in dogs (PK profile).

The bioavailability of 3 spray dried dispersions (ASD) was evaluated in a preclinical PK study in dogs. The following formulations - 25% belinostat in HPMCAS-M, PVPVA64 and PVPK30 are administered by oral gavage to 4 fasted male beagle dogs (7.0-9.0 kg) at a fixed dose of 50 mg per dog (equivalent to ~6.25 mg /kg). Animals were given one dose of each drug with a period between doses of at least one week.

After each dose, blood samples were taken from the jugular veins into heparinized tubes at the following time points: before giving the dose, after 5, 15 and 30 minutes, 1, 1.5, 2, 4, 6, 8, 12 and 24 hours. Plasma concentrations of belinostat were measured using a validated bioanalytical method (solid phase extraction, UHPLC-MS/MS, concentration range 1-1000 ng/mL).

The aim of the study was to evaluate whether the increase in solubility observed when dissolved in vitro leads to an increase in bioavailability compared to the crystalline form. The results are illustrated in the figure.

Intravenous dosing was performed to calculate absolute bioavailability and two control groups were added: crystalline drug in capsule as a poorly soluble drug control and oral solution (L-arginine intravenous formulation) as a best attainable concentration control without solubility limitation. It is important to note that due to the high pH (greater than 9.0) this oral solution is not pharmaceutically acceptable for clinical use.

Solutions of belinostat for intravenous administration and for oral administration are prepared as 50 mg/ml of belinostat in a solution of 100 mg/ml of L-arginine in water. The crystalline belinostat in a capsule is prepared by manually pouring 50 mg of belinostat (non-micronized) into a 2-part hard gelatin capsule of the appropriate size. ASD with belinostat is administered as suspensions of 40 mg/ml in 0.5% Methocel solution in an aqueous medium.

Pharmacokinetic parameters were derived from individual plasma concentration data using non-compartmental analysis with Phoenix WinNonlin (version 6.4).

C _max , AUC _0-24 and bioavailability (F%), calculated for each dog and then averaged for the test population, are shown in table. four.

Table 4. Pharmacokinetic parameters of amorphous spray-dried dispersion of belinostat in dogs

Preparations Actual Dose Range (mg/dog) AVERAGE Stach (ng/ml) Average AiSochgh (hour * ng / ml) Average bioavailability IV 42.2 -45.9 4210 (Co 7109) 1788 - Belinostat capsules 50.0-50.1 54 154 7% Oral solution (with L-arginine) 52.0-53.3 702 562 26% Spray-dried PVP VA64 dispersion 54.3-56.1 409 433 19% Spray-dried HPMCAS-M dispersion 43.9-45.3 338 443 25% Spray-dried PVP K30 dispersion 55.3-59.2 1053 653 28%

The oral solution is not suitable for oral administration.

HPMCAS-M is not suitable in any case as it is chemically unstable.

For capsules containing crystalline belinostat, the observed mean AUC( _0-12 h _a s) was 154 nghh/mL. For the suspension containing the belinostat/PVPK30 dispersion, the mean AUC was 4.2 times greater at 653 nghh/mL.

This example demonstrates that dosing of the spray-dried dispersion of belinostat/PVPK30 to dogs results in higher achieved belinostat concentrations than those observed after dosing of crystalline belinostat.

Such preparations of belinostat in the form of an amorphous solid dispersion with improved pharmacokinetic properties have not been known to date.

Claims (13)

1. An amorphous solid dispersion of belinostat containing: a) belinostat or a pharmaceutically acceptable salt, solvate or ester thereof; b) at least one vinyl lactam polymer; and c) optionally at least one additive. 2. The amorphous solid dispersion of belinostat according to claim 1, wherein said vinyl lactam polymer is selected from chain polymers and copolymers comprising the following subunit: - 16 039150 where m is an integer selected from 1, 2, 3 or 4 (β-, γ-, δ- or ε-lactam), and η is the number of repeating lactam units in the specified subunit. 3. Amorphous solid dispersion of belinostat according to claim 1 or 2, wherein said vinyl lactam polymer is water soluble. 4. Amorphous solid dispersion of belinostat according to any of pi. 1-3, wherein said vinyl lactam polymer is selected from the group consisting of polyvinyl pyrrolidone (PVP, povidone), PVP polyvinyl acetate (copovidone), and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-P V Ac-PEG). 5. An amorphous solid dispersion of belinostat according to any one of the preceding claims, wherein said vinyl lactam polymer is selected from PVP K30, PVP K12, PVP K25, PVP K90, PVP VA64 and mixtures thereof. 6. An amorphous solid dispersion of belinostat according to any one of the preceding claims, comprising: a) about 5-80% belinostat (mass percent); and b) about 20-95% of said vinyl lactam polymer (weight percent). 7. An amorphous solid dispersion of belinostat according to any one of the preceding claims, wherein said additive is selected from the group consisting of pH modifiers, antioxidants, dispersants, solubilizers, stabilizers, disintegrants, or any mixture thereof. 8. An amorphous solid dispersion of belinostat according to any one of the preceding claims, wherein said additive is histidine. 9. An amorphous solid dispersion of belinostat according to any one of the preceding claims, comprising less than 0.2% of belinostat acid and/or belinostat dimer according to the study at the time of completion of production; and/or less than 2% belinostat acid and/or belinostat dimer after storage for at least 18 months. 10. The method of obtaining an amorphous solid dispersion of belinostat according to any one of the preceding paragraphs, including the steps of obtaining a solution of belinostat and the specified vinyl lactam polymer in a solvent; drying said solution by spraying. 11. A pharmaceutical composition comprising the amorphous solid dispersion of belinostat according to any of the preceding claims and one or more pharmaceutically acceptable excipients. 12. Amorphous solid dispersion of belinostat according to any one of claims 1 to 9 for use in the treatment and/or prevention of cancer by oral administration. 13. Belinostat amorphous solid dispersion for use according to claim 12 for the treatment of lymphoma.